| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Renal Cell Carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced Renal Cell Carcinoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067946 |
| E.1.2 | Term | Renal cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. To compare MK-6482 to everolimus with respect to progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR)
2. To compare MK-6482 to everolimus with respect to overall survival (OS) |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare MK-6482 to everolimus with respect to objective response rate (ORR) based on RECIST 1.1 as assessed by BICR
2. To evaluate the duration of response (DOR) as assessed by BICR according to RECIST 1.1
3. To evaluate the safety and tolerability of MK-6482 compared to everolimus
4. To evaluate time to deterioration (TTD) and change from baseline in health-related quality of life (HRQoL) using the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire 30 (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy – Kidney Symptom Index-Disease-related Symptoms (FKSI-DRS)
5. To characterize health utility as measured using the European Quality of Life-5 dimensions-5 levels (EuroQoL EQ-5D-5L)
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Merck will conduct Future Biomedical Research on DNA (Blood, Tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
|
| E.3 | Principal inclusion criteria |
1. Has unresectable, locally advanced or metastatic clear cell RCC
2. Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
3. Has had disease progression on or after having received systemic treatment for locally advanced or metastatic RCC with both: PD-1/L1 checkpoint inhibitor and VEGF-TKI in sequence or in combination.
- PD-1/L1 checkpoint inhibitor treatment progression is defined by meeting ALL of the following criteria:
o Has received at least 2 doses of an anti- PD-1/L1 mAb
o Has demonstrated radiographic PD during or after an anti- PD-1/L1 mAb
-VEGF-TKI treatment progression is defined by meeting the following criteria:
-Has demonstrated radiographic PD during or after a treatment with a VEGF-TKI
4. Has received no more than 3 prior systemic regimens for locally advanced or metastatic RCC
5. For the most recently received regimen, has demonstrated radiographic disease progression
6. Is male or female, who is at least 18 years of age at the time of signing the informed consent
7. Has a KPS score of at least 70% assessed within 10 days prior to the first dose of study intervention randomization.
8. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 5 days after the last dose of study intervention:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent.
OR
• Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause as detailed below:
Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.
9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a WOCBP
OR
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 30 days after the last dose of study intervention for those randomized to the MK-6482 study intervention and for at least 8 weeks after last dose of study intervention for those randomized to the everolimus arm. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
• A WOCBP must have a negative highly sensitive pregnancy test (urine) as required by local regulations within 24 hours before the first dose of study intervention.
• If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy test is positive.
• Additional requirements for pregnancy testing during and after study intervention are located in the Schedule of Activities.
• The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
10. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for FBR. However, the participant may participate in the main study without participating in FBR
11. Has adequate organ function; all screening laboratory tests should be performed within 10 days prior to the first dose of study intervention randomization. |
|
| E.4 | Principal exclusion criteria |
1. A WOCBP who has a positive urine pregnancy test within 24 hours prior to randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
2. Has any of the following:
• Hypoxia as defined by pulse oximeter reading <92% at rest, OR
• Requires intermittent supplemental oxygen, OR
• Requires chronic supplemental oxygen.
3. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
4. Has known CNS metastases and/or carcinomatous meningitis
5. Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, or New York Heart Association Class III or IV congestive heart failure. Medically controlled arrhythmia stable on medication is permitted
6. Has poorly controlled hypertension defined as SBP ≥150 mm Hg and/or DBP ≥90 mm Hg
7. Has moderate to severe hepatic impairment (Child-Pugh B or C)
8. Received colony-stimulating factors (eg, G-CSF, GM-CSF or recombinant EPO) within 28 days prior to the first dose of study intervention randomization.
9. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
10. Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, malabsorption)
11. Has known hypersensitivity or allergy to the active pharmaceutical ingredient or any component of the study intervention (MK-6482 or everolimus) formulations
12. Has received prior treatment with MK-6482 or another HIF-2α inhibitor
13. Has received prior treatment with everolimus or any other specific or selective TORC1/PI3K/AKT inhibitor (eg, temsirolimus) in the advanced disease setting
14. Has received any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before randomization
15. Has received any type of systemic anticancer antibody (including investigational antibody) within 4 weeks before randomization
16. Has received prior radiotherapy within 2 weeks prior to randomization. Participants must have recovered from all radiation-related toxicities and not require corticosteroids. A 1-week washout is required for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease
17. Has had major surgery within 3 weeks prior to first dose of study intervention randomization.
18. Has received a live vaccine within 30 days prior to the randomization of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®/Fluenz Tetra)) are live attenuated vaccines and are not allowed
19. Is currently receiving either strong (eg, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (eg, ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of CYP3A4 that cannot be discontinued for the duration of the study
20. Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate (eg, bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study
21. Is currently receiving a drug that is a substrate of P-gp (eg, cyclosporin, elacridar, ketoconazole, quinidine, reserpine, ritonavir, tacrolimus, valspodar, verapamil, zosuquidar) that cannot be discontinued for the duration of the study
22. Is currently receiving a drug that is an inhibitor of P-gp (eg, cyclosporin, elacridar, ketoconazole, quinidine, reserpine, ritonavir, tacrolimus, valspodar, verapamil, zosuquidar) that cannot be discontinued for the duration of the study
23. Is currently participating in a study of an investigational agent or is currently using an investigational device
24. Has an active infection requiring systemic therapy
25. Has active TB
26. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization. Exception: Replacement corticosteroid therapy for adrenal or pituitary insufficiency is allowed.
27. Has a known history of HIV infection
28. Has a known history of HBV (defined as HBsAg reactive) or known active HCV (defined as HCV RNA [qualitative] is detected) infection
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
2. Overall Survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 47 months
2. Up to approximately 47 months |
|
| E.5.2 | Secondary end point(s) |
1. Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
2. Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
3. Number of Participants Who Experience One or More Adverse Events (AEs)
4. Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
5. Time to Deterioration in Health-Related Quality-of-Life (HRQoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Score
6. Time to Deterioration in Physical Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 1- 5 Score
7. Time to Deterioration in Disease Symptoms Using the Functional Assessment of Cancer Therapy – Kidney Symptom Index-Disease-related Symptoms (FKSI-DRS) Items 1-9 Score
8. Change From Baseline in Health-Related Quality-of-Life (HRQoL) Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 29 and 30 Score
9. Change From Baseline in Physical Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 1- 5 Score
10. Change From Baseline in Disease Symptoms Using the Functional Assessment of Cancer Therapy – Kidney Symptom Index-Disease-related Symptoms (FKSI-DRS) Items 1-9 Score
11. Change from Baseline in European Quality of Life 5 Dimensions, 5-level Questionnaire (EuroQoL EQ-5D-5L) Health Utility Score |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 47 months
2. Up to approximately 47 months
3. Up to approximately 47 months
4. Up to approximately 47 months
5. Up to approximately 47 months
6. Up to approximately 47 months
7. Up to approximately 47 months
8. Baseline (Day 1) and up to approximately 47 months
9. Baseline (Day 1) and up to approximately 47 months
10. Baseline (Day 1) and up to approximately 47 months
11. Baseline (Day 1) and up to approximately 47 months |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Chile |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Hong Kong |
| Hungary |
| Ireland |
| Italy |
| Japan |
| Korea, Republic of |
| Norway |
| Russian Federation |
| Spain |
| Taiwan |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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